Tissue factor as a potential coagulative/vascular marker in relapsing-remitting multiple sclerosis.

Objectives: Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities.

Methods: We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (=30; 23F/7M, 40 ± 8.

Alveolar Mitochondrial Quality Control During Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure and death in patients in the intensive care unit. Experimentally, acute lung injury resolution depends on the repair of mitochondrial oxidant damage by the mitochondrial quality control (MQC) pathways, mitochondrial biogenesis, and mitophagy, but nothing is known about this in the human lung. In a case-control autopsy study, we compared the lungs of subjects dying of ARDS (n = 8; cases) and age-/gender-matched subjects dying of nonpulmonary causes (n = 7; controls).

Survival outcomes for patients with colorectal cancer with synchronous liver only metastasis.

Background: Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear.

Methods: A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival.

GAT inhibition preserves cerebral blood flow and reduces oxidant damage to mitochondria in rodents exposed to extreme hyperbaric oxygen.

Oxygen breathing at elevated partial pressures (PO's) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO remains elevated during hyperbaric oxygen (HBO) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis).

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

Background: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part.

Methods: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021.

Nuclear respiratory factor-1 negatively regulates TGF-β1 and attenuates pulmonary fibrosis.

The preclinical model of bleomycin-induced lung fibrosis is useful to study mechanisms related to human pulmonary fibrosis. Using BLM in mice, we find low HO-1 expression. Although a unique Rhenium-CO-releasing molecule (ReCORM) up-regulates HO-1, NRF-1, CCN5, and SMAD7, it reduces TGFβ1, TGFβr1, collagen, α-SMA, and phosphorylated Smad2/3 levels in mouse lung and in human lung fibroblasts.

Prognostic Differences of RAS Mutations: Results from the South Australian Metastatic Colorectal Registry.

Background: Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome.

Regorafenib outcomes from the population based South Australian Metastatic Colorectal Cancer Registry.

Aim: Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry.

Methods: A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006.

The HO-1/CO System and Mitochondrial Quality Control in Skeletal Muscle.

Inducible heme oxygenase (HO)-1 catalyzes the breakdown of heme to biliverdin, iron, and carbon monoxide (CO). CO binds to cytochrome c oxidase and alters mitochondrial redox balance and coordinately regulates mitochondrial quality control (MQC) during oxidant stress and inflammation. The hypothesis presented is that the skeletal muscle HO-1/CO system helps modulate components in the MQC cycle during metabolic stress.

Case Report: Probable Cerebral Amyloid Angiopathy-Related Inflammation During Bevacizumab Treatment for Metastatic Cervical Cancer.

Bevacizumab is an anti-angiogenic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) that induces the proliferation and migration of vascular endothelial cells thus, promoting vasculogenesis. Bevacizumab inhibits cancer angiogenesis, which is fundamental for either tumor development, exponential growth, or metastatic spread by supplying nutrients and oxygen. We report a new possible adverse event of bevacizumab, a Cerebral Amyloid Angiopathy-Related Inflammation (CAARI), in a 72-year-old woman with metastatic cervical cancer.

Heparin-based blood purification attenuates organ injury in baboons with pneumonia.

Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to ) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and ) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with [5 × 10 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate ( = 6) or sham treatment ( = 6) for 4 h at 30 h after inoculation.

Rechallenge with Anti-EGFR Therapy in Metastatic Colorectal Cancer (mCRC): Results from South Australia mCRC Registry.

Background: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) are today increasingly used in the first- or second-line setting for RAS wild-type metastatic colorectal cancer (CRC) patients. Following progression beyond third- or fourth-line therapy, some patients are unsuitable for further chemotherapy because of poor performance status or patient choice. However, a significant number of patients are still candidates for further therapy despite limited standard options being available.

Skeletal muscle mitochondrial fragmentation and impaired bioenergetics from nutrient overload are prevented by carbon monoxide.

Nutrient excess increases skeletal muscle oxidant production and mitochondrial fragmentation that may result in impaired mitochondrial function, a hallmark of skeletal muscle insulin resistance. This led us to explore whether an endogenous gas molecule, carbon monoxide (CO), which is thought to prevent weight gain and metabolic dysfunction in mice consuming high-fat diets, alters mitochondrial morphology and respiration in C2C12 myoblasts exposed to high glucose (15.6 mM) and high fat (250 µM BSA-palmitate) (HGHF).

Carbon Monoxide and Exercise Prevents Diet-Induced Obesity and Metabolic Dysregulation Without Affecting Bone.

Objective: Carbon monoxide (CO) may counteract obesity and metabolic dysfunction in rodents consuming high-fat diets, but the skeletal effects are not understood. This study investigated whether low-dose inhaled CO (250 ppm) with or without moderate intensity aerobic exercise (3 h/wk) would limit diet-induced obesity and metabolic dysregulation and preserve bone health.

Methods: Obesity-resistant (OR) rats served as controls, and obesity-prone (OP) rats were randomized to sedentary, sedentary plus CO, exercise, or CO plus exercise.

Nonclassical Monocytes Sense Hypoxia, Regulate Pulmonary Vascular Remodeling, and Promote Pulmonary Hypertension.

An increasing body of evidence suggests that bone marrow-derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid cells in PH development has not been demonstrated, and a specific disease-promoting myeloid cell population has not been identified. Using bone marrow chimeras, lineage labeling, and proliferation studies, we determined that, in murine hypoxia-induced PH, Ly6C nonclassical monocytes are recruited to small pulmonary arteries and differentiate into pulmonary interstitial macrophages.

Mitochondrial DNA, oxidants, and innate immunity.

Mitochondrial oxidant damage, including damage to mitochondrial DNA (mtDNA) is a feature of both severe microbial infections and inflammation arising from sterile (non-infectious) sources such as tissue trauma. Damaged mitochondria release intact or oxidized fragments of mtDNA into the cytoplasm, which represent oxidant injury, and the fragments promote a spontaneous innate immune response, exemplifying a modern frontier of immunological research. MtDNA and mitochondrial-derived oxidants are central factors in activating at least three innate immune pathways involving the TLR9 (Toll-like receptor 9), the NLRP3 (NACHT, LRR and PYD domains-containing protein-3) inflammasome, and the cGAS (cyclic AMP-GMP synthase) pathway.

Tumefactive Demyelinating Lesions and Pregnancy.

Until now, only one gestational tumefactive demyelinating lesion (TDL) has been described. Here we report two TDL cases occurring during and after the pregnancy. A 26-year-old 6-week pregnant woman developed a 3-cm left frontotemporoparietal subcortical TDL with inhomogeneous partial enhancement.

Urinary excretion profile of prednisone and prednisolone after different administration routes.

The urinary excretion profile of prednisolone and prednisone after both systemic (i.e., oral) and topical (i.

Increased Antiseizure Effectiveness with Tiagabine Combined with Sodium Channel Antagonists in Mice Exposed to Hyperbaric Oxygen.

Hyperbaric oxygen (HBO) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO-induced seizures.

Peripheral Blood Mononuclear Cells Demonstrate Mitochondrial Damage Clearance During Sepsis.

Objectives: Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes.

Design: Prospective case-control study.

Outcomes for Metastatic Colorectal Cancer Based on Microsatellite Instability: Results from the South Australian Metastatic Colorectal Cancer Registry.

Background: Microsatellite instability (MSI) is the molecular marker for DNA mismatch repair deficiency (dMMR) in colorectal cancer (CRC) and has been associated with better survival outcomes in early stage disease. In metastatic CRC (mCRC), outcomes for patients with MSI are less clear. There is evolving evidence that treatment pathways for MSI CRC should include programmed-death 1 (PD-1) antibodies.

ABL kinase inhibition promotes lung regeneration through expansion of an SCGB1A1+ SPC+ cell population following bacterial pneumonia.

Current therapeutic interventions for the treatment of respiratory infections are hampered by the evolution of multidrug resistance in pathogens as well as the lack of effective cellular targets. Despite the identification of multiple region-specific lung progenitor cells, the identity of molecules that might be therapeutically targeted in response to infections to promote activation of progenitor cell types remains elusive. Here, we report that loss of specifically in SCGB1A1-expressing cells leads to a significant increase in the proliferation and differentiation of bronchiolar epithelial cells, resulting in dramatic expansion of an SCGB1A1+ airway cell population that coexpresses SPC, a marker for type II alveolar cells that promotes alveolar regeneration following bacterial pneumonia.

Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through β-Arrestin 1.

Background: Receptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors, which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for cross talk exist between these diverse signaling pathways.